PB0196 - Concizumab enhances thrombin generation potential in plasma from patients with FV-Amsterdam.

Sunday, June 25, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Rolf T. Urbanus, PhD

Associate professor
Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Utrecht, Utrecht, Netherlands

Co-Author(s)

Vv

Vossa van der Vegte

research technician
Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Utrecht, Utrecht, Netherlands
Roger E.G Schutgens, MD, PhD, MSc (he/him/his)

Internist-hematologist, Professor
Center for Benign Hematology, Thrombosis and Hemostasis, Van Creveldkliniek, University Medical Center Utrecht and University Utrecht, Utrecht, The Netherlands
Utrecht, Utrecht, Netherlands

Background: Factor V Amsterdam (FV-AMS) is a rare hereditary bleeding disorder caused by an aberrant FV-variant that readily binds and accumulates tissue factor pathway inhibitor (TFPI) in plasma. The resulting high TFPI levels impair coagulation. Concizumab is a humanized monoclonal anti-TFPI antibody blocking TFPI-mediated inhibition of factor Xa currently under investigation in phase III trials for treatment of haemophilia. Whether concizumab treatment would also be feasible in FV-AMS is unknown.

Aims: To evaluate the effects of concizumab on thrombin generation in plasma from patients with FV-AMS.

Methods: Plasma was obtained from 2 patients with FV-AMS and 23 healthy controls. FV-AMS plasma was spiked with concizumab. Thrombin generation parameters were analyzed with calibrated automated thrombography at 1 pM TF. Ethics approval was obtained. All participants provided informed consent.

Results: Total TFPI levels were elevated in both patients with FV-AMS (521 and 860 ng/mL compared with 97(SD 21) ng/mL in controls). Thrombin generation initiated with 1 pM TF was absent in both patients. Addition of concizumab restored thrombin generation in a dose-dependent manner, with maximal effects at 20 nM or higher in both subjects (figure 1). At 20 nM, endogenous thrombin potentials in both subjects were normal (1090 and 570 nM thrombin x min, compared with 1007 (range 394-1604) nM thrombin x min in healthy controls). However, peak height (57 nM and 39 nM) remained low compared with healthy controls (264; range 42-306 nM). Initiation of coagulation was slower in both subjects (lag time 13.0 min and 11.5 min) than in healthy controls (8.5 min; range 3.2-11.7) as well.

Conclusion(s): Concizumab enhances thrombin generation in plasma from patients with FV-AMS with optimal effects at 20 nM or higher. Whether treatment of FV-AMS with concizumab is feasible remains to be determined.

Concizumab was kindly provided by Novo Nordisk A/S